1. Field of the Invention
The invention relates to development of cancer drug, especially relates to the development of novel 1,2-disubstituted amido-anthraquinone derivatives, preparation method and application thereof.
2. Description of the Prior Art
Telomere
A telomere is a region of repetitive DNA at the end of a chromosome, which protects the end of the chromosome from deterioration, recombination, and end-to-end fusion. Telomere is composed of short and repeated DNA sequences. A high percentage of guanine (G) is present in this DNA sequence from 5′-end to 3′-end. The telomere DNA sequence (TTAGGG)n is conserved among vertebrates, including human.
In normal somatic cell, the terminal end of the chromosome will lose a part of RNA primer after each replication, and will shorten off about 50-60 bp after each cell division. When the telomere is shortened to a certain extent, cell will go to apoptosis, this phenomenon is called an end-replication problem of a cell.
Telomerase
Telomerase is the enzyme that synthesizes telomeric DNA, the terminal DNA at chromosome ends which, together with telomere-binding proteins, confers stability to chromosomes. In most of organism, the replication and maintenance of the length of telomere has to rely on telomerase. The telomerase is composed of RNA and protein subunits. At present, part of important telomerase subunits had been identified. The composition of human telomerase comprising: human telomerase reverse transcriptase (hTERT) having reverse transciptase activity, human telomerase RNA component used as a template, and some telomere-binding proteins such as human telomerase-associated protein, p23, hsp90, hsp40, hsp70 and the like.
Many research studies had indicated that the activity of human telomerase can only be detected in cells having high proliferation ability, for example, germ cells, hemopoietic cells, part of stem cells, most of immortalized cells and most of tumor cells. In the somatic cell, the telomere will be shorten gradually as the number of cell division increased, which may be considered as the mitotic clock for counting the number of cell division. When a telomere is shortened to a certain extent, cell will stop division and entering aging stage, stay at this stage for a period of time, and then goes to death. This period of time is called mortality stage 1 (M1 stage). When a tumor suppressor gene such as p53 or Rb is mutated within M1 stage, the cell might escape from aging stage and keeps on cell division in this period of time which is called mortality stage 2 (M2 stage). If a cell lacks of telomerase activity during this period, the length of a telomere will be reduced still, the telomere will not be able to protect the terminal end of the chromosome, and this might result into the instability of the chromosome, as well as the cell can not transfer genetic information completely and enters apoptosis in the end. Therefore, M2 stage is also called a crisis stage. Most of cells will die in M2 stage, except small part of cells with telomerase activity will be survived. This small part of cells will continue to divide without limitation and become an immortalized cell (or a cancer cell).
In view of the foregoing, it is thought generally that the activation of telomerase can maintain the length of a telomere so as to prevent a cell from entering the ageing stage; or the inhibition of telomerase activity can be used to limit the division of a cancer cell. Both thought may become the key factors in the development of a cell toward immortalization or cancerization. In summary, using the telomerase inhibitors to treat the cancer have been considered as a novel cancer-specific therapy, as most tumor cells have high expression of telomerase, whereas most normal somatic cells express low or undetectable levels of telomerase and is therefore an attractive target for the design of anticancer agents.
Anthraquinone-containing extracts from different plant sources such as senna, cascara, aloe, frangula, and rhubarb have been found to have wide variety of pharmacological activities such as anti-inflammatory, wound healing, analgesic, antipyretic, antimicrobial, and antitumor activities. And some of the anthraquinone derivatives had also shown the antitumor activity. Therefore, many investigators consider them as highly promising lead candidates in drug design.
In view of the importance of the development of cancer therapy drugs, the invention provides the inventive 1,2-disubstituted amido-anthraquinone derivatives, preparation method and application thereof.